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ESMO 2020 | Ripretinib IPDE following disease progression in GIST

Filip Janku, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, TX, discusses results from a Phase I study (NCT02571036) in which ripretinib intra-patient dose escalation (IPDE) following disease progression provided clinically meaningful progression-free survival (PFS) in gastrointestinal stromal tumor (GIST). The Phase III INTRIGUE study (NCT03673501) will evaluate ripretinib vs sunitinib in 2nd-line GIST. This interview was recorded via an online conference call with The Video Journal of Oncology (VJOncology).

Transcript (edited for clarity)

I had the pleasure, on behalf of my co-investigators, to present very exciting data from a study which tested a switch pocket inhibitor ripretinib of the KIT and PDGFRA kinase, using the intrapatient dose escalation in patients with gastrointestinal stromal tumor.

Ripretinib, as I just pointed out, is a switch control inhibitor which is actually effective on a broad spectrum of KIT mutations, including mutations which are deemed to be resistant to other tyrosine kinase inhibitors inhibiting KIT...

I had the pleasure, on behalf of my co-investigators, to present very exciting data from a study which tested a switch pocket inhibitor ripretinib of the KIT and PDGFRA kinase, using the intrapatient dose escalation in patients with gastrointestinal stromal tumor.

Ripretinib, as I just pointed out, is a switch control inhibitor which is actually effective on a broad spectrum of KIT mutations, including mutations which are deemed to be resistant to other tyrosine kinase inhibitors inhibiting KIT. Ripretinib entered the clinical arena in the phase one clinical study in November 2015, and due to pretty a fast drug development timeline, actually was FDA approved for patients with gastrointestinal stromal tumor who failed three prior therapies or more in May of this year. So, it was actually a pretty quick drug development timeline.

The data which I presented at ESMO was an extension of the initial phase one study. The death phase one study allowed patients with developed disease progression on the recommended phase two dose, which ultimately ended up being also the FDA-approved dose. So, these patients were actually allowed to escalate to ripretinib 150 milligrams twice-a-day, which is a dose that is twice as high as the FDA-approved dose/recommended phase two dose in the study. And, out of 142 patients who received the recommended phase two dose, 150 milligrams daily, ultimately 67 at progression were escalated to the dose of 150 milligrams, twice-a-day.

And quite interestingly, in these stations, we have seen quite meaningful progression-free survival. So, if I can just point out the progression-free survival for the ripretinib 150 milligrams daily, which was 11 months for patients who received ripretinib in the second line, 8.3 months for patients who received ripretinib in the third line, and 5.5 months for patients who received ripretinib in fourth or more lines. In ripretinib 150 milligrams twice-a-day, with patients progressing on daily dosing, doubling the dose actually again led to quite meaningful progression-free survival of which was 5.6 months for the second line, 3.3 months for the third line, and 4.6 months for the fourth or more lines, which was actually quite intriguing.

Responses were relatively infrequent after intrapatient dose escalation. We, in fact, have seen only one patient who attained PR after the dose was escalated, but also side effects were quite acceptable. So, the side effect profile of daily dosing and analysis of daily and double dosing actually showed a very similar side effect profile. Not necessarily there’s any significant tendency to more adverse events based on increased dosing.

So, I think, our observation, in summary, suggests that escalation of the dose of ripretinib at the time of disease progression can actually add some additional mileage in terms of progression-free survival and might be a meaningful strategy for patients developing adaptive resistance to ripretinib. The treatment-emergent adverse events were acceptable. They were maybe slightly more frequent, but we analyzed the twice-a-day dosing and the once-a-day dosing together and they are still in a very similar ballpark. So, I’m finding this concept quite interesting because, essentially, if you can get some additional progression-free survival just by increasing the dose, that can be added on already meaningful progression-free survival. Basically, I think the daily dosing is actually something which can be a potentially very interesting strategy for these patients who otherwise have limited treatment options.

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